Global DNA hypomethylation in epithelial ovarian cancer: passive demethylation and association with genomic instability

AbstractA hallmark of human cancer is global DNA hypomethylation (GDHO), but the mechanisms accounting for this defect and its pathological consequences have not been defined in human epithelial ovarian cancer (EOC). In EOC, GDHO was associated with advanced disease and reduced overall and disease-free survival. GDHO(+) EOC was enriched for a proliferative gene expression signature, including CCNE1 and FOXM1 overexpression. DNA hypomethylation preferentially occurred within genomic blocks (hypomethylated blocks) overlapping late-replicating, lamina-associated domains, PRC2 binding, and H3K27me3. Increased proliferation coupled with hypomethylated block formation at late replicating regions suggested passive hypomethylation, which was further supported by the observation that cytosine DNA methyltransferases (DNMTs) and UHRF1 showed significantly reduced expression in GDHO(+) EOC, after normalization to proliferation markers. Importantly, GDHO(+) EOC showed elevated chromosomal instability (CIN), and copy number alterations (CNA) were enriched at hypomethylated blocks. Together, these findings implicate a passive demethylation mechanism for GDHO that promotes genomic instability and poor prognosis in EOC.

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Global DNA Hypomethylation in Epithelial Ovarian Cancer: Passive Demethylation and Association with Genomic Instability

Cancers ◽

10.3390/cancers12030764 ◽

2020 ◽

Vol 12 (3) ◽

pp. 764 ◽

Cited By ~ 4

Author(s):

Wa Zhang ◽

David Klinkebiel ◽

Carter J. Barger ◽

Sanjit Pandey ◽

Chittibabu Guda ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Genomic Instability ◽

Human Cancer ◽

Disease Free Survival ◽

Gene Expression Signature ◽

Dna Methyltransferases ◽

Dna Demethylation ◽

Dna Hypomethylation ◽

Proliferation Markers

A hallmark of human cancer is global DNA hypomethylation (GDHO), but the mechanisms accounting for this defect and its pathological consequences have not been investigated in human epithelial ovarian cancer (EOC). In EOC, GDHO was associated with advanced disease and reduced overall and disease-free survival. GDHO (+) EOC tumors displayed a proliferative gene expression signature, including FOXM1 and CCNE1 overexpression. Furthermore, DNA hypomethylation in these tumors was enriched within genomic blocks (hypomethylated blocks) that overlapped late-replicating regions, lamina-associated domains, PRC2 binding sites, and the H3K27me3 histone mark. Increased proliferation coupled with hypomethylated blocks at late-replicating regions suggests a passive hypomethylation mechanism. This hypothesis was further supported by our observation that cytosine DNA methyltransferases (DNMTs) and UHRF1 showed significantly reduced expression in GDHO (+) EOC after normalization to canonical proliferation markers, including MKI67. Finally, GDHO (+) EOC tumors had elevated chromosomal instability (CIN), and copy number alterations (CNA) were enriched at the DNA hypomethylated blocks. Together, these findings implicate a passive DNA demethylation mechanism in ovarian cancer that is associated with genomic instability and poor prognosis.

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Interval Debulking Surgery After Neodjuvant Chemotherapy Vs Primary Debulking Surgery For Stage Iii Epithelial Ovarian Carcinoma

Tumori Journal ◽

10.1177/0300891620914135 ◽

2020 ◽

Vol 106 (1_suppl) ◽

pp. 15-15

Author(s):

BM Ahmed ◽

AT Amin ◽

MK Khallaf ◽

A Ahmed Refaat ◽

SA Sileem

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Disease Free Survival ◽

Figo Stage ◽

Stage Iii ◽

Debulking Surgery ◽

Free Survival ◽

Primary Debulking Surgery ◽

Interval Debulking Surgery ◽

Disease Free

Introduction: Ovarian cancer is the most lethal gynecologic malignancy and is the fifth most common cause of cancer-related death among women. Approach to FIGO stage III epithelial ovarian cancer remains challengeable. This study aims to evaluate the outcome of interval debulking surgery (IDS) vs. primary debulking surgery (PDS) for FIGO stage III epithelial ovarian cancer. Materials and Methods: During a period of six years (January 2014 to December 2019), we analyzed the patients for eligibility criteria, which were: (1) FIGO stage III epithelial ovarian cancer. (2) The age of 18 years or more (3) Patients underwent either PDS or IDS and received chemotherapy at South Egypt Cancer Institute. We divided them into two groups: (1) Those received three cycles of neoadjuvant chemotherapy and then underwent IDS plus three additional cycles of adjuvant chemotherapy and (2) Those who have PDS followed by six cycles of chemotherapy. Results: This study includes 380 eligible patients. The first group included 226 patients (59.47%) underwent PDS then 6 cycles of chemotherapy, while the group of IDS included 154 patients (40.53%). The treatment modality was not significant for overall survival (OS); however disease-free survival (DFS) was significantly reduced after IDS when compared to PDS (median DFS: 33 months; 95% CI 30.23-35.77 vs. 45 months; 95% CI 41.25-48.75 respectively; p= .000). Moreover, in subgroup analysis, OS and DFS were significantly dropped after IDS in elderly patients, patients with bad performance status, sub-optimal cytoreduction as well as high grade and undifferentiated tumors when compared to those who underwent PDS. Conclusion: Although treatment modality may not impact overall survival (OS), however, PDS results in a better disease-free survival than IDS. Moreover, IDS results in a significant drop in OS and DFS in special patients subgroups when compared to PDS. Therefore patients selection should be considered.

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Erratum to: Anesthetic Selection and Disease-Free Survival Following Optimal Primary Cytoreductive Surgery for Stage III Epithelial Ovarian Cancer

Annals of Surgical Oncology ◽

10.1245/s10434-015-4542-z ◽

2015 ◽

Vol 22 (S3) ◽

pp. 1611-1611

Author(s):

Kevin M. Elias ◽

Stephanie Kang ◽

Xiaoxia Liu ◽

Neil S. Horowitz ◽

Ross S. Berkowitz ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Cytoreductive Surgery ◽

Disease Free Survival ◽

Stage Iii ◽

Free Survival ◽

Disease Free

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Expression of hypoxia-inducible factor 1α gene affects the outcome in patients with ovarian cancer

International Journal of Gynecological Cancer ◽

10.1111/j.1525-1438.2007.01055.x ◽

2008 ◽

Vol 18 (3) ◽

pp. 499-505 ◽

Cited By ~ 29

Author(s):

R. SHIMOGAI ◽

J. KIGAWA ◽

H. ITAMOCHI ◽

T. IBA ◽

Y. KANAMORI ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Hypoxia Inducible Factor ◽

Disease Free Survival ◽

High Expression ◽

Vegf Expression ◽

Free Survival ◽

Hypoxia Inducible Factor 1Α ◽

Disease Free ◽

Low Expression

We conducted study to determine whether and how the expression of the hypoxia-inducible factor 1α (HIF-1α) gene relates to outcome in patients with epithelial ovarian cancer. A total of 66 patients with epithelial ovarian cancer, who underwent primary surgery followed by platinum-based chemotherapy, were entered into this study. We confirmed the expression of HIF-1α and the vascular endothelial growth factor (VEGF) by immunohistochemistry. To determine the quantity of HIF-1α and VEGF expression, messenger RNA of each gene was measured by real-time reverse transcription–polymerase chain reaction. The cutoff values were determined by the receiver-operating characteristic curve according to survival. The protein expressions of HIF-1α and VEGF were strongly observed in the cancer cells. The cutoff value of HIF-1α and VEGF gene expression was 6.0 and 3.0, respectively. The expression of HIF-1α did not relate to clinical stage, but tumor with low VEGF expression was observed more frequently in stage I patients. The response rate to chemotherapy did not differ between high and low expression of both genes. The overall survival for patients with high expression of HIF-1α was significantly lower, but disease-free survival did not differ between high and low expression of HIF-1α, whereas both overall and disease-free survival for patients with high expression of VEGF were significantly lower. Multivariate analysis revealed that FIGO stage and HIF-1α expression were independent prognostic factors but that VEGF was not. The present study suggested that the expression level of HIF-1α could be an independent prognostic factor in epithelial ovarian cancer

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